Pyogenic liver abscesses associated with nonmetastatic colorectal cancers: An increasing problem in Eastern Asia

Abstract

AIM: To elaborate the clinicopathologic features of colorectal cancer-related pyogenic liver abscess (PLA).

METHODS: Reported cases of colorectal cancer-related PLAs were collected from the literature published up to October 2011 and evaluated for their clinicopathologic features. Data of collected cases included demographics, clinical presentation, microbial findings and treatment. Categorical variables were compared by χ² analysis and continuous variables were evaluated using Student’s t test.

RESULTS: A total 96 cases of colorectal cancer-related PLA were collected from the previous literature. Most patients (60%) were male and 40% cases occurred in the age group of 61-70 years. Apart from some special types of PLA, there were significant differences in the microbiological spectrum between Eastern Asia and non-Eastern Asian countries, which implied different risk factors and courses of the disease. Gram negative bacteria especially Klebsiella pneumoniae (K. pneumoniae) PLA was predominant in Eastern Asia (80.0%) in contrast to non-Eastern Asian countries (P < 0.01). Meanwhile, most of the Eastern Asian patients exhibited smaller size of liver abscess and atypical presentation. Sigmoid colon and rectum (72.73%) were the main sites of tumor in Eastern Asian patients, whereas tumor sites were uneven among most of the non-Easter Asian PLA patients.

CONCLUSION: K. pneumoniae PLA was strongly associated with colorectal cancer, especially those occurring in sigmoid colon and rectum, in elderly Eastern Asian male patients.

Key Words: Colorectal cancer, Pyogenic liver abscess, Etiology, Microbiology, Treatment

INTRODUCTION

Liver is the most common organ to develop abscesses. Pyogenic liver abscess (PLA), once predominantly a disease of young adults as a consequence of post-appendicitis pylephlebitis, nowadays occurs more frequently in elderly patients, with hepatobiliary tract diseases or intra-abdominal infections including cholecystitis, suppurative cholangitis, suppurative pylephlebitis, diverticulitis and peritonitis[1]. Meanwhile, as we cannot find significant underlying causes of PLA, the term “cryptogenic abscesses” is used. For all types of PLA, mucosal defect present within digestive tract lesions or a compromised mucosal barrier allowing a route for bacteria invasion into the portal system with subsequent hematogenous spread to the liver is regarded as the key process[2].

Previous studies revealed that a few cryptogenic PLA patients were related to neoplasms[3]. This type of PLA was regarded as a warning indicator of silent cancers. Recently, many cases of PLA associated with nonmetastatic colorectal carcinoma have been reported worldwide. Interestingly, this PLA in Eastern Asia seems to have greater morbidity and exhibits differences in clinical characteristics. However, there were few studies which analyzed this phenomenon, neither was there any recommendation or consensus for treatment. Therefore, we reviewed published case reports from worldwide literature and retrospectively investigated the etiology, clinical characteristics and treatment of PLA complicated with nonmetastatic colorectal carcinoma.

MATERIALS AND METHODS

Source of data

Data from the available medical literature were systematically reviewed and pooled to analyze. MEDLINE (United States National Library of Medicine, Bethesda, MD), EMBASE (Elsevier Science, New York, NY) and CNKI National Knowledge Infrastructure) bibliographic databases were searched and relevant studies in form of case-control studies, case series or case report published in English language were retrieved using the keywords: “hepatic/liver abscess”, “malignant cancer”, “colorectal cancer” or “bacterium”. The relevant article references in English and other languages were also collected.

Data extraction and quality control

A medical information scientist performed the literature retrieval and the initial screening of relevant studies, and a medical doctor reviewed and coded all studies. Cases were scrutinized to exclude any duplicate reports of the same patients. Many studies reported only aggregate results. Whenever possible, data were extracted both at an aggregate level within each study and at a patient level. The individual cases without individual identification were also excluded. We excluded studies or individuals with missing data from specific analyses. As a result, the number of patients in each analysis varied.

Database

The collected cases were evaluated individually, and details were extracted and computerized for further analysis. Coded potential prognostic determinants included patient demographics, microbial, clinical and laboratory findings, and the authors’ affiliations. The data were pooled at both the aggregate and patient levels to determine the distribution of the underlying disease, site of infection, and other pertinent variables.

Statistical analysis

All collected data were transcribed into a Microsoft Excel spreadsheet and analyzed using SPSS software, version 14.0 (SPSS). Continuous variables were compared using analysis of variance, and categorical variables were compared using the χ² test. P < 0.05 was regarded as significantly different.

RESULTS

Removing irrelevant articles, and articles published in internal journal and reviews, we collected a total of 32 articles with 96 cases from 623 publications in the international literature up to September 2011. Two case-control studies[4,5] and 30 case reports[3,6-34] were included. Most of articles were single case report (26/32). Sixteen cases included in aggregate series[2,15,27-31,33] and 32 cases with individual information summarized in one article published in Japanese were also extracted[7]. Among the 32 collected articles, 25 articles were in English, 2 were in Japanese, 1 was in Chinese, 1 was in Spanish, 1 was in French and 1 was in Hebrew.

Global distribution of reported cases

Although cases of colorectal cancer-related PLA were originally reported in Western countries[2,27-31,33], most of reported cases (80.21%) were published in the Eastern Asian countries/regions, especially in Japan (40 cases), China (26 cases) and Korea (8 cases) (Table 1). The reported number of colorectal cancer-related PLA has increased significantly over the past two decades. Approximately, 90% patients have been reported since 1990 after colonoscopy and percutaneous transhepatic abscess drainage (PTAD) became common in clinical practice. In Eastern Asian countries/regions, the number of cases was increasing rapidly, with a growth rate of approximately 4-5 times every decade from 1981 to 2011 (Figure 1).

Table 1 Documented cases collected from the international literature.

Country/region	No. of cases	No. of articles
Eastern Asia
Japan	40	36[6-10]1
China	26	6[4,5,11-14]
Korea	8	1[15]
Singapore	3	1[16]
Middle East and Europe
Israel	3	3[17-19]
Italy	2	2[20,21]
Spain	2	2[22,23]
Portugal	1	1[24]
France	1	1[25]
United Kingdom	1	1[26]
North and Central America
United States	7	7[2,27-32]
Canada	1	1[33]
Netherlands Antilles	1	1[34]
Total	96	63

¹Other 33 cases reported in a Japanese article reference were included[8].

Figure 1 Growth trend of reported cases in different countries/regions from 1960 to 2011.

Demographical evaluation

The average age of the patients in the present series was 64.4 ± 10.1 years. A male-to-female ratio of 1.5:1 was calculated for the overall series and for patients of different areas. There was no significant difference in the average age between gender groups (male 65.0 years vs female 63.4 years, P > 0.05) and geographical groups (Eastern Asia 64.6 years vs non-Eastern Asia 63.3 years, P > 0.05). In the overall series from both Eastern Asia and non-Eastern Asian groups, approximately 40% patients fell into the age groups of 61-70 years (Figure 2).

Figure 2 Age distribution of reported cases in different countries/regions.

Microbiology

According to bacteria culture results from 58 patients, Klebsiella pneumoniae (K. pneumoniae) was the most common pathogen (50.0%), followed by Fusobacterium species (6.90%), Streptococcus species (6.90%), Bacteroides species (5.17%), Enterococcus faecium (3.44%), Escherichia coli (3.44%) and Pseudomonas aeruginosa (3.44%). There were two cases of amoebic liver abscess and two cases with mixed infection. In addition, 10 patients had negative results of pus cultures (Table 2). There was a significant difference between Eastern Asian and non-Eastern Asian groups in gram stains of pathogens. Among the gram-negative pathogens, K. pneumoniae was more dominant in Eastern Asian than in non-Eastern Asian groups (Figure 3).

Table 2 Constituent ratio of pus bacterial cultures n (%).

Pathogens	Eastern Asia	Non-Eastern Asia	Total
	(n = 49)	(n = 9)	(n = 58)
Bacteria
Gram negative bacteria
Klebsiella pneumoniae	28 (57.14)	1 (11.1)	29 (50.0)
Fusobacterium species	4 (8.16)	0	4 (6.90)
Bacteroides species	2 (4.08)	1 (11.1)	3 (5.17)
Escherichia coli	0	1 (11.1)	1 (1.72)
Pseudomonas aeruginosa	1 (2.04)	0	1 (1.72)
Gram positive bacteria
Streptococcus species	1 (2.04)	3 (33.3)	4 (6.90)
Enterococcus faecium	2 (4.08)	0	2 (3.44)
Polymicrobial	0	2 (22.2)1	2 (3.44)
Amoebae	2 (4.08)	0	2 (3.44)
Negative	9 (18.37)	1 (11.1)	10 (17.24)

¹Pus cultures showed mixed infection in two patients: E. corrodens, Candida albicans and Candida glabrata; Peptostreptococcus anaerobius, Bacteroides melaninogenicus and Peptostreptococcus spp.

Figure 3 Categorization of pathogens in Eastern Asian and non-Eastern Asian patients. A: Distribution of Gram-negative and Gram-positive pathogens; B: Distribution of Klebsiella pneumoniae (K.P) and non-K.P. There were significant differences in categories of pathogens between Eastern Asian and non-Eastern Asian patients (P < 0.01).

Morphologic characteristics of liver abscess

All liver abscess cases were finally diagnosed with B-mode ultrasonic and/or computed tomography scanning. According to the image results of the 66 patients, 66.7% abscesses formed in the right liver lobe, 18.2% in the left lobe and 12.1% in two lobes (Figure 4). There was no significant difference in the location of liver abscess between Eastern Asian and non-Eastern Asian groups (Figure 5). Thirty-one reported cases had individual data of liver abscess size, which was 5.31 ± 2.11 cm on average. The average abscess size of Eastern Asian patients was smaller than that of non- Eastern Asian patients (P < 0.05). Moreover, there was no significant difference in the average size between gender groups, age groups and pathogen groups (Figure 6).

Figure 4 Distribution of colorectal cancer and liver abscesses.

Figure 5 Probability of abscess in different liver lobes in Eastern Asian and non-Eastern Asian patients. There was no significant difference between the two groups (P > 0.05).

Figure 6 Univariate analysis of abscess size in colorectal cancer related pyogenic liver abscess patients. A: Abscess sizes in different geographical groups; B: Abscess sizes in different gender groups; C: Abscess sizes in different age groups; D: Abscess sizes in different pathogenic groups. There was significant difference in liver abscess sizes between Eastern Asian and non-Eastern Asian patients (P < 0.05). K.P: Klebsiella pneumoniae.

Clinical manifestations and diagnosis

The clinical manifestation of 25 patients was pyogenic liver abscess, including fever and chill (92.0%), abdominal pain (68.0%), abdominal tenderness (64.0%) and nausea/vomiting (45.0%). No more than 40% patients had the chief complaint of atypical symptoms of tumor, which included anemia (40.0%) and weight loss (32.0%). Only approximately 10% of the patients had bowl cancer symptoms, including bloody stool (12.0%) and alterations in bowel habits (4.0%) (Figure 7). None of the cases had abdominal mass, and the digital rectal examinations were negative. Infection indices of the 25 patients with details of laboratory examination revealed a significantly increased level of white blood cell count (17.9-5.22 × 10⁹/L) and C-reactive protein (17.8 ± 7.49 mg/dL); and a moderately elevated level of alanine aminotransferase and total bilirubin. However, colorectal cancer-related biomarkers (including CA19-9 and carcinoembryonic antigen) did not elevate in most of the patients.

Figure 7 Clinical presentations of colorectal cancer related pyogenic liver abscess patients.

Monitoring of occult colorectal cancers

Most of the diagnoses of colorectal cancer were made by coloscopy (77.3%) and barium enema (29.2%). The most common site of tumor formation was sigmoid colon (40.9%), followed by rectum (27.3%), ascending (18.2%), transverse (7.6%) and descending colon (6.0%) (Figure 4). Among the 23 patients with pathological reports, colorectal adenocarcinoma (81.8%) and medium differentiation degree (66.7%) were the most common pathological type and differentiation degree, respectively. There was no difference between Eastern Asian and non-Eastern Asian groups in the sites of colon tumors. However, tumors occurred more often in sigmoid colon and rectum in Eastern Asia group (Figure 8).

Figure 8 Probability of cancer in different colorectal regions in Eastern Asian and non-Eastern Asian patients. A: Probability of cancer appeared in the right and left hemi-colon; B: Probability of cancer in sigmoid and rectum and other regions. Sigmoid and rectum were the more common cancer sites, compared with other regions (P < 0.05).

Treatment for colorectal cancer-related PLA

All of the patients were treated with broad-spectrum antibiotics. The most commonly used antibiotics were cephalosporins with or without metronidazole, followed by fluoroquinolones with or without metronidazole, ampicillin and gentamicin, carbapenems, and gentamicin (Table 3). PTAD was extremely successful as initial treatment for liver abscess. The type of treatment (antibiotics combined with/without PTAD) chosen may have been influenced by several factors (e.g., clinician/radiologist’s decision and others). There was no significant difference in the distribution of demographic characteristics (age, gender, geographic distribution and pathogens) between the study and the comparison groups (Table 4). Until the date of the submission of the report, 17 patients had been followed up for an average of 15.4 ± 15.44 mo, all were kept stable with no tumor recurrence.

Table 3 Treatment for liver abscess complicated with colorectal carcinoma.

Sex	Age, yr	Count of abscess	Anti-infection treatment	Surgical treatment	Ref.
Female	46	Mutiple1	Cephalosporin	Sigmoidectomy	[4]
Female	79	Single	Carbapenem	PTAD + low anterior rectal resection	[5]
Male	66	Single	Broad spectrum antibiotic6	PTAD + low anterior rectal resection	[6]
Male	73	Single	Broad spectrum antibiotic6	PTAD + sigmoidectomy	[7]
Male	65	Single	Broad spectrum antibiotic6	PTAD	[7]
Male	67	Single	Broad spectrum antibiotic6	PTAD	[7]
Male	81	Mutiple	Broad spectrum antibiotic6	Laparoscopic-assisted sigmoidectomy	[8]
Male	67	Mutiple2	Cephalosporin	PTAD + polypectomy under colonscopy	[11]
Male	67	Single	Broad spectrum antibiotic6	PTAD + polypectomy under colonscopy	[12]
Female	84	Single	Broad spectrum antibiotic6	None7	[12]
Female	82	Mutiple3	Cephalosporin	PTAD + sigmoidectomy	[13]
Female	57	Single	Cephalosporin + carbapenem + moxifloxacin + gentamicin	PTAD + sigmoidectomy + chemotherapy	[14]
Female	68	Single	Cephalosporin	PTAD + low anterior rectal resection	[16]
Male	67	Single	Cephalosporin	Polypectomy under colonscopy	[16]
Male	77	Single4	Cephalosporin + ciprofloxacin + gentamicin	PTAD7	[16]
Female	66	Single	Broad spectrum antibiotic6	PTAD + sigmoidectomy	[18]
Male	64	Single	Broad spectrum antibiotic6	PTAD + right hemi-colectomy + partial hepatectomy	[19]
Male	60	Mutiple	Piperacillin + aminoglycoside	Right hemi-colectomy	[20]
Female	50	Single	Broad spectrum antibiotic6	Right hemi-colectomy + partial hepatectomy + chemotherapy	[21]
Male	68	Three	Amoxicillin + clavulanic acid	PTAD + sigmoidectomy	[22]
Male	72	Single	Cephalosporin + metronidazole + gentamicin	PTAD + right hemi-colectomy	[23]
Male	64	Two	Cephalosporin + metronidazole	Sigmoidectomy and radiotherapy	[24]
Female	82	Single	Cephalosporin +metronidazole	PTAD	[26]
Male	52	Mutiple5	Broad spectrum antibiotic6	Sigmoidectomy + chemotherapy + gemcitabine	[32]
Male	55	Single	Ampicillin + sulbactam + gentamicin	PTAD + sigmoidectomy	[34]

¹Patient had endophthalmitis with brain, lung abscesses complicated with liver abscesses;

²Patient developed S. bovis bacteremia with complications of endocarditis, osteomyelitis and silent splenic abscess after four episodes of Klebsiella pneumoniae liver abscess within 3 years;

³Patient experienced three episodes of liver abscess within 1 year;

⁴Complicated with pulmonary infections;

⁵Patient experienced two episodes of liver abscess within 3 mo;

⁶Details were not recorded;

⁷Patients refused to have further treatments. PTAD: Percutaneous transhepatic abscess drainage.

Table 4 Different therapy for colorectal cancer related liver abscess patients n (%).

	No. of patients		P value
	Antibiotics alone(n = 16)	Antibiotics + drainage (n = 42)
Gender			0.057
Male	13 (81.2)	23 (54.8)
Female	3 (18.8)	19 (45.2)
Age (yr)			0.631
< 60	2 (12.5)	5 (11.9)
> 60	14 (87.5)	37 (88.1)
Geographic distribution			0.564
Eastern Asia	13 (81.2)	35 (83.3)
Non-Eastern Asia	3 (18.8)	7 (16.7)
Pathogen			0.498
K. pneumoniae	6 (37.5)	14 (33.3)
Non-K. pneumoniae	16 (62.5)	28 (66.7)

K. pneumoniae: Klebsiella pneumoniae.

DISCUSSION

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women all over the world. Previous studies have reported rapid increases in colorectal cancer incidence rates, especially in economically transitioning countries[35,36]. Many Eastern Asian countries, such as China, Japan, South Korea, and Singapore, have experienced a 2-4 folds increase in the incidence of colorectal cancer during the past few decades[37]. Common manifestations of colon cancer are alteration in bowel habit, rectal bleeding and abdominal pain. Besides, liver abscess during the course of an undiagnosed colon cancer may also occur as the initial manifestation of the disease, even without associated metastasis. This PLA had been reported worldwide and was regarded as the herald of colorectal cancers.

Recently, the number of new cases of colorectal cancer-related PLA is soaring in Eastern Asia, and this trend is worthy of concern. We found that 80% of the reported cases in the whole world occurred in the Eastern Asian countries, especially in Japan, China and Korea. The demographic features of the Eastern Asian and non-Eastern Asian patients in this study were non-specific. The mean age was 64.4 years, and male to female ratio was about 1.5:1. However, microbiological feature was different between Eastern Asian and non-Eastern Asian patients. The bacteriologic analysis in our series revealed that K. pneumoniae was the most common pathogen in Eastern Asian patients. Our observation was also consistent with the entire incidence of K. pneumoniae PLA in Eastern Asian population[38-40].

Clinical features of the colorectal cancer-related PLA patients in this study were non-specific. The most common clinical presentations were fever, chills, abdominal pain, and nausea or vomiting. In contrast, only 10% patients had bowl cancer symptoms and the diagnosis of colorectal cancer was extremely difficult. Colonoscopy was considered as an effective screening method for diagnosis of colorectal cancer. Most (77.3%) of colorectal cancer patients in our study were confirmed by colonoscopy. The colon site of tumor mostly involved was the sigmoid colon (40.9%), followed by the rectum (27.3%), ascending colon (18.2%), transverse colon (7.6%) and descending colon (6.0%). There was significant difference of tumor site between Eastern Asian and non-Eastern Asian patients. Thus, Eastern Asian physicians should be vigilant in monitoring colorectal cancers, especially in the sigmoid colon and rectum.

In our case series, before colorectal cancers were found, several patients had experienced recurrence of PLA after PTAD treatment[13,15,32]. Destruction of the mucosal barrier of colon and the repeated bacterial translocation was the pathogenesis of liver abscesses in such patients. Thus, although broad spectrum antibiotics combined with PTAD as first-line treatment for the management of PLA had been accepted by most physicians[41], operative intervention for colorectal lesions remains crucial. Meanwhile, in the elderly with recurrent cryptogenic PLA, colonoscopy is suggested and required to avoid misdiagnosis of colorectal cancer.

To our knowledge, this is the first attempt to systemically review the cases of colorectal cancer-related PLA worldwide. However, there still remain limitations to our retrospective study. Incomplete data collection was found during our review of literatures. Some clinical features appeared to have been overlooked; in particular, the relatively non-specific clinical symptoms were missing. In addition, although more reported cases were observed in Eastern Asian than non Eastern Asian countries, the real incidence of colorectal cancer-related PLA is still unknown. Epidemiological investigation with a larger sample size is needed for further analysis.

In conclusion, colorectal cancer-related PLA is an increasing life-threatening disease in Eastern Asia in the recent two decades. In the absence of significant manifestation, the search for the underlying cause of the pyogenic liver abscess should be an integral part of the management of liver abscesses. The association with a colorectal cancer is rare but should be taken into consideration. Early and appropriate surgical treatment can achieve good prognosis.

ACKNOWLEDGMENTS

We thank Dr. Ying Yang from Tangdu Hospital for her critical review and revision of the manuscript. This study was done as a collaborative work of researchers who have long been involved in the field of liver abscess complicated with colorectal cancers. Therefore, sincere thanks for those who supported all prior pilot studies in this field.

COMMENTS

Background

Colorectal cancers related-pyogenic liver abscess (PLA) is a special hepatic infection and regarded as the herald of colon cancer. Recent publications from Eastern Asia revealed a considerable morbidity in this region. Knowledge of etiology and clinical features, when possible, play an important role in the successful treatment of colorectal cancers-related PLA patients.

Research frontiers

PLA, once occurs more frequently in elderly patients with hepatobiliary tract disease or intra-abdominal infections. Recently, many cases of PLA associated with nonmetastatic colorectal carcinomas have been reported in the worldwide. Interestingly, this PLA in Eastern Asia seems to have a greater morbidity and exhibits differences in clinical characteristics. However, there have been few studies to analyze this phenomenon.

Innovations and breakthroughs

This is the first attempt to systemically review the cases of colorectal cancer-related PLA worldwide. A total of 96 cases of colorectal cancers-related PLAs were collected from the international literature and evaluated in clinicopathologic features. This study results revealed that Klebsiella pneumoniae (K. pneumoniae) PLA was tightly related with colorectal cancer (especially those located in sigmoid colon and rectum) in elderly Eastern Asian males.

Applications

By understanding the different clinicopathological features between patients from Eastern Asia and non-Eastern Asia countries, this study may represent a future strategy for therapeutic intervention in the treatment of patients with colorectal cancer-related PLA.

Terminology

PLA, occurs more frequently in elderly patients with hepatobiliary tract diseases or intra-abdominal infections. For all types of PLA, mucosal defects present within digestive tract lesions are regarded to be the key process. Recent studies revealed that a few PLA patients were related to neoplasms. This type of PLA exhibited different features and was regarded as a warning indicator of silent cancers.

Peer review

The authors reviewed the literature to evaluate features of colorectal cancer-related pyogenic liver abscess. It revealed that there was clear differences in the microbiological spectrum between Asian and non-Asian cases. Gram-negative bacteria especially K. pneumoniae PLA was predominant in Eastern Asia. Meanwhile, most of the Eastern Asian patients exhibited smaller size of liver abscess and atypical presentation. Sigmoid colon and rectum were the main sites of tumor in these patients. The results are interesting and may represent a clear understanding of colorectal cancer-related PLA in Eastern Asian patients.